Process of producing 2-iminothiazoline derivatives and process of producing their intermediates

ABSTRACT

There is disclosed a process of producing a 2-iminothiazoline derivative of the general formula  II!, characterized in that a thiourea derivative of the general formula  I! is treated with an acid. Also disclosed are a process of producing an N-substituted N-arylcyanamide derivative of the general formula  VI!, characterized in that an N-arylcyanamide derivative of the general formula  IV! is reacted with an allyl halide derivative of the general formula  V! in an aprotic polar solvent in the presence of an iodide and an alkali metal carbonate; and a process of producing an N-substituted N-arylthiourea derivative of the general formula  VII!, characterized in that an N-substituted N-arylcyanamide derivative of the general formula  VI! obtained as described above is further reacted with a chemical species which generates sulfide ion or hydrogensulfide ion.

This application is a divisional of copending application Ser. No.08/434,589, filed on May 4, 1995, the entire contents of which arehereby incorporated by reference; which was a divisional of applicationSer. No. 08/160,261, filed on Dec. 2, 1993, now U.S. Pat. No. 5,463,069the entire contents of which are hereby incorporated by reference.

The present invention relates to a process of producing2-iminothiazoline derivatives that are useful as intermediates for theproduction of medicaments and agricultural chemicals, particularly asintermediates for the production of herbicidal compounds (see, e.g.,U.S. Pat. No. 5,244,863 and European Patent Publication No. 0529482A).The present invention also relates to a process of producing someintermediates for the production of these 2-iminothiazoline derivatives.

As a conventional process of producing 2-iminothiazoline derivatives,for example, there is a process of the following scheme as described inJ. Chem. Soc. Perkin Trans. I, 3, 639 (1987): ##STR1##

This process has a disadvantage of having poor regioselectivity in thereaction as depicted in the above scheme and can only find particularlyapplications; therefore, it is not always satisfactory as a process ofproducing 2-iminothiazoline derivatives.

The present inventors have intensively studied a production process for2-iminothiazoline derivatives of the general formula II! as depictedbelow, and found that such 2-iminothiazoline derivatives can be obtainedby acid treatment of thiourea derivatives of the general formula I! asdepicted below, thereby completing the present invention.

Thus, the present invention provides a process of producing a2-iminothiazoline derivative of the general formula: ##STR2## wherein R¹is optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl or optionally substituted heteroaryl; R² ishydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedalkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionallysubstituted arylcarbonyl, optionally substituted alkoxycarbonyl,optionally substituted cycloalkyloxycarbonyl or optionally substitutedaryloxycarbonyl; and R³, R⁴ and R⁵ are the same or different, each ofwhich is hydrogen, optionally substituted alkyl or optionallysubstituted aryl, the process comprising the step of treating a thioureaderivative of the general formula: ##STR3## wherein R¹, R², R³, R⁴ andR⁵ are each as defined above and X is halogen, with an acid.

Also provided is a process of producing an N-substituted N-arylcyanamidederivative of the general formula: ##STR4## wherein R³, R⁴, R⁵ and X areeach as defined above and R¹² is optionally substituted aryl, theprocess comprising the step of reacting an N-arylcyanamide derivative ofthe general formula: ##STR5## wherein R¹² is as defined above, with anallyl halide derivative of the general formula: ##STR6## wherein R³, R⁴,R⁵ and X are each as defined above and Y¹ is chlorine or bromine, in anaprotic polar solvent in the presence of an iodide and an alkali metalcarbonate.

Further provided is a process of producing an N-substitutedN-arylthiourea derivative of the general formula: ##STR7## wherein R³,R⁴, R⁵, R¹² and X are each as defined above, the process comprising thestep of reacting an N-substituted N-arylcyanamide derivative of thegeneral formula: ##STR8## wherein R³, R⁴, R⁵, R¹² and X are each asdefined above, with a chemical species which generates sulfide ion orhydrogensulfide ion.

The process of producing a 2-iminothiazoline derivative according to thepresent invention is characterized in that a particular thioureaderivative is subjected to acid treatment.

In the present invention, typical examples of the R¹ are C₁₋₈ alkyloptionally substituted with at least one substituent (e.g., C₁₋₈ alkoxy,aryl, C₃₋₈ cycloalkyl, etc.); C₃₋₈ cycloalkyl optionally substitutedwith at least one substituent (e.g., C₁₋₈ alkyl, C₁₋₈ alkoxy, aryl,etc.); aryl optionally substituted with at least one substituent (e.g.,C₁₋₈ alkyl optionally substituted with at least one halogen atom; C₃₋₈alkoxy optionally substituted with at least one halogen atom; aryl,nitro, halogen, etc.); and heteroaryl optionally substituted with atleast one substituent (e.g., C₁₋₈ alkyl optionally substituted with atleast one halogen atom; C₁₋₈ alkoxy optionally substituted with at leastone halogen atom; aryl, nitro, halogen, etc.).

Typical examples of the R² are hydrogen, C₁₋₈ alkyl optionallysubstituted with at least one substituent (e.g., C₁₋₈ alkoxy, aryl, C₃₋₈cycloalkyl, etc.); C₃₋₈ cycloalkyl optionally substituted with at leastone substituent (e.g., C₁₋₈ alkyl, C₁₋₈ alkoxy, aryl, etc.); aryloptionally substituted with at least one substituent (e.g., C₁₋₈ alkyl,C₁₋₈ alkoxy, aryl, nitro, halogen, etc.); alkyl (C₁₋₈) carbonyloptionally substituted with at least one substituent (e.g., C₁₋₈ alkoxy,aryl, C₃₋₈ cycloalkyl, etc.); cycloalkyl (C₃₋₈) carbonyl optionallysubstituted with at least one substituent (e.g., C₁₋₈ alkyl, C₁₋₈alkoxy, aryl, etc.); arylcarbonyl optionally substituted with at leastone substituent (e.g., C₁₋₈ alkyl, C₁₋₈ alkoxy, aryl, nitro, halogen,etc.); alkoxy (C₁₋₈) carbonyl optionally substituted at least onesubstituent (e.g., C₁₋₈ alkoxy, aryl, C₃₋₈ cycloalkyl, etc.); cycloalkyl(C₃₋₈) oxycarbonyl optionally substituted with at least one substituent(e.g., C₁₋₈ alkyl, C₁₋₈ alkoxy, aryl, etc.); and aryloxycarbonyloptionally substituted with at least one substituent (e.g., C₁₋₈ alkyloptionally substituted with at least one halogen atom; C₁₋₈ alkoxyoptionally substituted with at least one halogen atom; aryl, nitro,halogen, etc.).

Typical examples of each of the R³, R⁴ and R⁵ are hydrogen, C₁₋₈ alkyloptionally substituted with at least one substituent (e.g., C₁₋₈ alkoxy,aryl, C₃₋₈ cycloalkyl, etc.); and aryl optionally substituted with atleast one substituent (e.g., C₁₋₈ alkyl, C₁₋₈ alkoxy, aryl, nitro,halogen, etc.).

In the above examples, the term "alkyl" means a member of alkyl groupssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, hexyl and octyl; the term "cycloalkyl" means a member ofcycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cyclooctyl; the term "alkoxy" means a member of alkoxygroups such as methoxy, ethoxy, propyloxy, isopropyloxy, butoxy,isobutyloxy, sec-butyloxy, tert-butyloxy, hexyloxy and octyloxy; theterm "aryl" means a member of aryl groups such as phenyl, α-naphthyl andβ-naphthyl; the term "heteroaryl" means a member of heteroaryl groupssuch as pyridyl, pyrimidinyl, thienyl, imidazolyl, thiazolyl andoxazolyl; and the term "halogen" means a member of halogen atoms such aschlorine, bromine, iodine and fluorine. As also used therein, the term"optionally substituted with at least one substituent" or "optionallysubstituted with at least one halogen atom" means that at least one(e.g., one to three) hydrogen atoms on each group may be optionallyreplaced by the same or different substituents or halogen atoms,respectively. As the X, chlorine or bromine is usually used.

Specific examples of the thiourea derivative of the general formula I!used as a starting material in the present invention are as follows:

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea;

N-(3,5-dichlorophenyl)-N-(2-chloro-2-propenyl)thiourea;

N-(4-methoxyphenyl)-N-(2-chloro-2-propenyl)thiourea;

N-(3-chlorophenyl)-N-(2-chloro-2-propenyl)thiourea;

N-(3-(trifluoromethoxy)phenyl)-N-(2-chloro-2-propenyl)thiourea;

N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea;

N-butyl-N-(2-chloro-2-propenyl)-N'-phenylthiourea;

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-1-methyl-2-propenyl)thiourea;

N-(2-chlorophenyl)-N-(2-chloro-2-propenyl)thiourea;

N-(3-(trifluoromethyl)phenyl)-N-(2-bromo-2-propenyl)thiourea;

N-butyl-N-(2-chloro-2-propenyl)-N'-butylthiourea;

N-butyl-N-(2-chloro-2-propenyl)-N'-benzylthiourea;

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-butenyl)thiourea;

N-(3-(trifluoromethoxy)phenyl)-N-(2-chloro-2-butenyl)thiourea; and

N-(4-fluoro-3-(trifluoromethoxy)phenyl)-N-(2-chloro-2-butenyl)thiourea.

Specific examples of the 2-iminothiazoline derivative of the generalformula II! are as follows:

2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline;

2-imino-3-(3,5-dichlorophenyl)-5-methyl-4-thiazoline;

2-imino-3-(4-methoxyphenyl)-5-methyl-4-thiazoline;

2-imino-3-(3-chlorophenyl)-5-methyl-4-thiazoline;

2-imino-3-(3-(trifluoromethoxy)phenyl)-5-methyl-4-thiazoline;

2-imino-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline;

2-(N-phenylimino)-3-butyl-5-methyl-4-thiazoline;

2-imino-3-(3-(trifluoromethyl)phenyl)-4,5-dimethyl-4-thiazoline;

2-imino-3-(2-chlorophenyl)-5-methyl-4-thiazoline;

2-(N-butylimino)-3-butyl-5-methyl-4-thiazoline;

2-(N-benzylimino)-3-butyl-5-methyl-4-thiazoline;

2-imino-3-(3-(trifluoromethyl)phenyl)-5-ethyl-4-thiazoline;

2-imino-3-(3-(trifluoromethoxy)phenyl)-5-ethyl-4-thiazoline; and

2-imino-3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-ethyl-4-thiazoline.

As the acid used in the present invention, there can be mentionedprotonic acids, metal salts having Lewis acidity, and mixtures thereof.

In one embodiment of the acid treatment according to the presentinvention, a 2-iminothiazoline derivative of the general formula II! canbe obtained by treatment of a thiourea derivative of the general formulaI! with a protonic acid having strong acidity.

Typical examples of the protonic acid having strong acidity are sulfuricacid (usually having a concentration of 100% to 50%, preferably 100% to75%); inorganic acids having acidity which is equal to or stronger thanthat of sulfuric acid; and organic acids having strong acidity, such astrifluoromethanesulfonic acid, methanesulfonic acid and trifluoroaceticacid.

The reaction is usually carried out without any solvent, but an inertsolvent against the acid may be used. Examples of the solvent which canbe used in the reaction are aliphatic hydrocarbon solvents such asheptane and hexane; aromatic hydrocarbon solvents such as benzene,toluene and xylene; halogenated hydrocarbon solvents such asmonochlorobenzene, chloroform and ethylene dichloride; carboxylic acidsolvents such as formic acid and acetic acid; and mixtures thereof. Thereaction is usually carried out at a temperature of 0° to 150° C.,preferably 20° to 120° C., for 0.2 to 24 hours. The protonic acid havingstrong acidity is usually used at a proportion of 1 to 1000 moles to onemole of the thiourea derivative of the general formula I!.

After completion of the reaction, water is added to the reactionmixture, which is then neutralized by addition of an alkali, and theneutralized mixture is subjected to an ordinary post-treatment such asextraction with an organic solvent and concentration, and if necessary,any purification such as chromatography may be further utilized to givethe desired 2-iminothiazoline derivative of the general formula II!.

In another embodiment of the acid treatment according to the presentinvention, a 2-iminothiazoline derivative of the general formula II! canbe obtained by treatment of a thiourea derivative of the general formulaI! with a metal salt having Lewis acidity, and if necessary, a protonicacid.

Typical examples of the metal salt having Lewis acidity are stannichalides such as stannic chloride (SnCl₄), stannic bromide (SnBr₄) andstannic iodide (SnI₄); zinc halides such as zinc chloride (ZnCl₂), zincbromide (ZnBr₂) and zinc iodide (ZnI₂); cupric halides such as cupricchloride (CuCl₂); and aluminum halides such as aluminum chloride(AlCl₃). These metal salts are not always required to be in anhydrousform, and they may contain crystal water.

Typical examples of the protonic acid are inorganic acids such ashydrochloric acid and sulfuric acid; and organic acids such asmethanesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonicacid. The addition of such a protonic acid is not always required whenthe metal salt having Lewis acidity is solvolized in the reaction systemto form a protonic acid.

The reaction is usually carried out in a solvent. Typical examples ofthe solvent which can be used in the reaction are aliphatic hydrocarbonsolvents such as heptane and hexane; aromatic hydrocarbon solvents suchas benzene, toluene and xylene; halogenated hydrocarbon solvents such asmonochlorobenzene, chloroform and ethylene dichloride; ether solventssuch as dimethoxyethane, tetrahydrofuran and dioxane; carbonyl solventssuch as acetone and methyl isobutyl ketone; alcohol solvents such asmethanol and ethanol; 1,3-dimethyl-2-imidazolidone,N,N-dimethylformamide, dimethylsulfoxide, and mixtures thereof. Thereaction is usually carried out at a temperature of 0° to 150° C.,preferably 20° to 120° C., for 0.2 to 24 hours. The metal salt havingLewis acidity is usually used at a proportion of 0.01 to 20 moles,preferably 0.2 to 2 moles, taking into the consideration the effects onthe post-treatment and reaction rate, to one mole of the thioureaderivative of the general formula I!. The protonic acid is usually usedat a proportion of 1 to 100 moles to one mole of the thiourea derivativeof the general formula I!.

After completion of the reaction, water is added to the reactionmixture, which is then neutralized by addition of an alkali, and ifnecessary, followed by treatment such as filtration; the neutralizedmixture is subjected to an ordinary post-treatment such as extractionwith an organic solvent and concentration, and if necessary, anypurification such as chromatography may be further utilized to give thedesired 2-iminothiazoline derivative of the general formula II!.

In still another embodiment of the acid treatment according to thepresent invention, a 2-iminothiazoline derivative of the general formulaII! can be obtained by reaction of a thiourea derivative of the generalformula I! in the presence of a metal salt having Lewis acidity to givea 2-iminothiazolidine derivative of the general formula: ##STR9##wherein R¹, R², R³, R⁴ and R⁵ are each as defined above (the step ishereinafter referred to as "Reaction A") and by treatment of the2-iminothiazolidine derivative of the general formula III! with aprotonic acid (the step is hereinafter referred to as "Reaction B").

Typical examples of the metal salt having Lewis acidity which can beused in Reaction A are stannic halides such as stannic chloride (SnCl₄),stannic bromide (SnBr₄) and stannic iodide (SnI₄); zinc halides such aszinc chloride (ZnCl₂), zinc bromide (ZnBr₂) and zinc iodide (ZnI₂);cupric halides such as cupric chloride (CuCl₂); and aluminum halidessuch as aluminum chloride (AlCl₃). These metal salts are not alwaysrequired to be in anhydrous form, and they may contain crystal water.

Reaction A is usually carried out in a solvent. Typical examples of thesolvent which can be used in the reaction are aliphatic hydrocarbonsolvents such as heptane and hexane; aromatic hydrocarbon solvents suchas benzene, toluene and xylene; halogenated hydrocarbon solvents such asmonochlorobenzene, chloroform and ethylene dichloride; ether solventssuch as dimethoxyethane, tetrahydrofuran and dioxane; carbonyl solventssuch as acetone and methyl isobutyl ketone; alcohol solvents such asmethanol and ethanol; 1,3-dimethyl-2-imidazolidone,N,N-dimethylformamide, dimethylsulfoxide, and mixtures thereof. ReactionA is usually carried out at a temperature of 0° to 150° C., preferably50° to 120° C., for 0.2 to 24 hours. The metal salt having Lewis acidityis usually used at a proportion of 0.01 to 20 moles, preferably 0.2 to 2moles, taking into the consideration the effects on the post-treatmentand reaction rate, to one mole of the thiourea derivative of the generalformula I!.

Typical examples of the protonic acid which can be used in Reaction Bare inorganic acids such as hydrochloric acid and sulfuric acid; andorganic acids such as methanesulfonic acid, trifluoroacetic acid andtrifluoromethanesulfonic acid.

Reaction B is usually carried out in a solvent. Typical examples of thesolvent which can be used in Reaction B are aliphatic hydrocarbonsolvents such as heptane and hexane; aromatic hydrocarbon solvents suchas benzene, toluene and xylene; halogenated hydrocarbon solvents such asmonochlorobenzene, chloroform and ethylene dichloride; ether solventssuch as dimethoxyethane, tetrahydrofuran and dioxane; carbonyl solventssuch as acetone and methyl isobutyl ketone; alcohols such as methanoland ethanol; carboxylic acid solvents such as acetic acid andtrifluoroacetic acid; 1,3-dimethyl-2-imidazolidone,N,N-dimethylformamide, dimethylsulfoxide, water, and mixtures thereof.Reaction B is usually carried out at a temperature of 0° to 150° C.,preferably 20° to 100° C., for 0.2 to 24 hours. The protonic acid isusually used at a proportion of 1 to 100 moles to one mole of the2-iminothiazolidine derivative of the general formula III!.

More specifically, in the treatment with a protonic acid, the isolated2-iminothiazolidine derivative of the general formula III! may betreated, or the reaction mixture after completion of the reaction of athiourea derivative of the general formula I! with a metal salt havingLewis acidity may be treated in the presence of the metal salt havingLewis acidity.

After completion of Reaction A or B, water is added to the reactionmixture, which is then neutralized by addition of an alkali, and ifnecessary, followed by treatment such as filtration; the neutralizedmixture is subjected to an ordinary post-treatment such as extractionwith an organic solvent and concentration, and if necessary, anypurification such as chromatography may be further utilized to give thedesired compound of the general formula III! or II!.

The thiourea derivative of the general formula I! used as a staringmaterial in the present invention can be obtained, for example, by aprocess of the following scheme: ##STR10## wherein R¹, R², R³, R⁴, R⁵and R⁶ are each as defined above and Y is a leaving group such aschlorine, bromine, mesyloxy or tosyloxy.

The following Examples 1 to 11 will illustrate the process of producing2-iminothiazoline derivatives according to the present invention, butthese examples are not to be construed to limit the scope thereof.

The purity of a product was determined from the results of NMRspectroscopy and liquid chromatography. If the product exhibited nopeaks of impurities in NMR spectroscopy and liquid chromatography, thisproduct was determined to be pure.

The yield of a product was determined from the weight of the isolatedproduct or by the external standard method using liquid chromatography(i.e., LC-ES method) or the internal standard method using gaschromatography (i.e., GC-IS method).

In the LC-ES method, the detection intensity of an isolated purematerial, which was the same as a product to be measured, at a specifiedconcentration was obtained by liquid chromatography; after completion ofthe reaction, the reaction mixture was adjusted to a specifiedconcentration, and the detection intensity of the product was obtainedby liquid chromatography; finally, the yield was calculated from boththe detection intensities thus obtained. The liquid chromatography wascarried out through a reverse-phase column ODS A 212 (manufactured bySumika Chemical Analysis Service, Ltd.) with phosphate buffered aqueoussolution (pH 7.2): methanol: tetrahydrofuran=40:55:5 as an eluent and anultraviolet-visible absorption detector for detection at the wavelengthof 254 nm.

In the GC-IS method, the detection intensity ratio of an isolated purematerial, which was the same as a product to be measured, and aninternal standard material (biphenyl) was obtained by gaschromatography; after completion of the reaction, a specified amount ofthe internal standard material was added to the reaction mixture, andthe detection intensity ratio of the product and the internal standardmaterial was obtained by gas chromatography; finally, the yield wascalculated from both the detection intensity ratios thus obtained. Thegas chromatography was carried out through a capillary column DB-1having a wide bore (0.53 mm×30 m; manufactured by J & W Scientific) withhelium gas as a carrier at a rate of 10 ml/min.

EXAMPLE 1

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (1.00 g)was added to 98% sulfuric acid (9.96 g) at room temperature withstirring, and the mixture was heated to 90° C. and stirred at the sametemperature for 1.0 hour. After cooling, ice-water was added to thereaction mixture, which was then neutralized by addition of sodiumcarbonate and extracted with ethyl acetate. The organic layer was washedwith water. The solvent was removed by distillation under reducedpressure, which afforded 0.835 g of2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline as an oil(81% yield as a corrected value from the below-mentioned purity). Fromthe results of analysis by liquid chromatography, the purity wasdetermined to be 85%.

¹ H-NMR (CDCl₃ /TMS) δ (ppm): 7.9-7.5 (4H, m), 6.3 (1H, q), 5.3 (1H,br), 2.1 (3H, d).

Mass Spectrum (FD): Parent ion peak at (m/e) 258.

EXAMPLE 2

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (29.5 mg)was added to 90% sulfuric acid (1.0 ml) at room temperature withstirring, and the mixture was heated to 90° C. and stirred at the sametemperature for 1 hour. After cooling, the reaction mixture was dilutedwith ice-water and acetonitrile to a specified concentration. With theLC-ES method, the yield of2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline wasdetermined to be 60%.

EXAMPLE 3

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (29.5 mg)was added to trifluoromethanesulfonic acid (1.0 ml) at room temperaturewith stirring, and the mixture was stirred at 25° C. for 1 hour. Aftercooling, the reaction mixture was diluted with ice-water andacetonitrile to a specified concentration. With the LC-ES method, theyield of 2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline wasdetermined to be 86%.

EXAMPLE 4

N-(3,5-dichlorophenyl)-N-(2-chloro-2-propenyl)thiourea (0.30 g) wasadded to 90% sulfuric acid (3.5 g) at room temperature with stirring,and the mixture was heated to 90° C. and stirred at the same temperaturefor 1.0 hour. After cooling, water was added to the reaction mixture,which was then neutralized by addition of sodium hydrogen carbonate andextracted with ethyl acetate. The organic layer was washed with water.The solvent was removed by distillation under reduced pressure, and theresidual oily material was subjected to column chromatography on silicagel, which afforded 0.16 g of2-imino-3-(3,5-dichlorophenyl)-5-methyl-4-thiazoline (62% yield).

¹ H-NMR (CDCl₃ /TMS) δ (ppm): 7.4 (2H, d), 7.2 (1H, t), 6.3 (1H, q), 5.3(1H, br), 2.0 (3H, d).

EXAMPLE 5

N-butyl-N-(2-chloro-2-propenyl)-N'-phenylthiourea (0.26 g) was added to90% sulfuric acid (2.5 g) at room temperature with stirring, and themixture was heated to 50° C. and stirred at the same temperature for 1.5hour. After cooling, water was added to the reaction mixture, which wasthen neutralized by addition of sodium hydrogen carbonate and extractedwith ethyl acetate. The organic layer was washed with water. The solventwas removed by distillation under reduced pressure, which afforded 0.09g of 2-(N-phenylimino)-3-butyl-5-methyl-4-thiazoline as an oil (34%yield).

¹ H-NMR (CDCl₃ /TMS) δ (ppm): 7.4-7.2 (5H, m), 6.5 (1H, q), 4.1 (2H, t),2.0 (3H, d), 1.8 (2H, tt), 1.4 (2H, tq), 1.0 (3H, t).

EXAMPLE 6

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (2.94 g)and zinc chloride (6.08 g) were added to xylene (50 ml) at roomtemperature, and the mixture was heated to 90° C. and stirred at thesame temperature for 1.5 hour. After cooling, water was added to thereaction mixture, which was neutralized by addition of potassiumhydrogen carbonate and extracted with ethyl acetate. The organic layerwas washed with water. The solvent was removed by distillation underreduced pressure, and the residual oil was subjected to preparativeliquid chromatography, which afforded 1.92 g of2-imino-3-(3-(trifluoromethyl)phenyl)-5-methylidenethiazolidine (74%yield). From the results of analysis by liquid chromatography, thepurity was determined to be not lower than 99%.

¹ H-NMR (CDCl₃ /TMS) δ (ppm): 7.9-7.3 (4H, m), 6.9 (1H, br), 5.3 (1H,dd), 5.1 (1H, dd), 4.6 (2H, t).

Mass Spectrum (FD): Parent ion peak at (m/e) 258.

The 2-imino-3-(3-(trifluoromethyl)phenyl)-5-methylidenethiazolidine.thus obtained (29.4 mg) was added to 90% sulfuric acid (0.5 ml), and themixture was heated to 40° C. and stirred at the same temperature for 1hour. After cooling, the reaction mixture was neutralized by addition ofsodium hydrogen carbonate and extracted with ethyl acetate. The organiclayer was washed with water and concentrated by distillation of thesolvent under reduced pressure. The concentrate was dissolved togetherwith biphenyl in acetonitrile. With the GC-IS method, the yield of2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline wasdetermined to be 98% (on the basis of2-imino-3-(3-trifluoro-methyl)phenyl)-5-methylidenethiazolidine).

The 2-imino 3-(3-(trifluoromethyl)phenyl)-5-methylidenethiazolidine thusobtained (29.4 mg) was added to 35% hydrochloric acid (0.5 ml), and themixture was heated to 40° C. and stirred at the same temperature for 1hour. After cooling, the reaction mixture was neutralized by addition ofsodium hydrogen carbonate and extracted with ethyl acetate. The organiclayer was washed with water and concentrated by distillation of thesolvent under reduced pressure. The concentrate was dissolved togetherwith biphenyl in acetonitrile. With the GC-IS method, the yield of2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline wasdetermined to be 96% (on the basis of2-imino-3-(3-(trifluoromethyl)phenyl)-5-methylidenethiazolidine).

EXAMPLE 7

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (29 mg)and zinc bromide (63 mg) were added to xylene (about 2 g) at roomtemperature, and the mixture was heated to 90° C. and stirred at thesame temperature for 1 hour. After cooling, the reaction mixture wasdiluted with water and acetonitrile to a specific concentration. Withthe LC-ES method, the yield of2-imino-3-(3-(trifluoromethyl)phenyl)-5-methylidenethiazolidine wasdetermined to be 85%.

The 2-imino-3-(3-(trifluoromethyl)phenyl)-5-methylidenethiazolidine thusobtained is converted into2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline in the samemanner as described in the latter half of Example 9.

EXAMPLE 8

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thioure (294 mg)and anhydrous stannic chloride (24 μl) were added to trifluoroaceticacid (1.0 ml) at room temperature, and the mixture was heated to 75° C.and stirred at the same temperature for 3 hours. After cooling, waterwas added to the reaction mixture, neutralized by addition of sodiumhydrogen carbonate, and diluted with acetonitrile to a specifiedconcentration. With the LC-ES method, the yield of2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline wasdetermined to be 84%.

EXAMPLE 9

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (1.47 g)and stannic chloride n-hydrate (n=4 to 5) (0.09 g) were added to methylisobutyl ketone (7.50 g) at room temperature, and the mixture was heatedto 90° C. and stirred at the same temperature for 7 hours. Aftercooling, 35% hydrochloric acid (0.52 g) was added to the reactionmixture with stirring, and the mixture was heated to 90° C. and stirredat the same temperature for 2.5 hours. After cooling, water was added tothe reaction mixture, which was then neutralized by addition of sodiumhydrogen carbonate and extracted with methyl isobutyl ketone. Theorganic layer was washed with water. The solvent was removed bydistillation under reduced pressure, which afforded 1.08 g of2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline (75% yieldas a corrected value from the below-mentioned purity). From the resultsof analysis by liquid chromatography, the purity was determined to be89%.

EXAMPLE 10

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (295 mg)and zinc chloride (64 mg) were added to methyl isobutyl ketone (2.50 g)at room temperature, followed by addition of 35% hydrochloric acid (100mg) at room temperature with stirring, and the mixture was heated to 90°C. and stirred at the same temperature for 9 hours. After cooling, zincchloride (137 mg) was further added to the reaction mixture withstirring, and the mixture was heated to 90° C. and stirred at the sametemperature for 2 hours. After cooling, the reaction mixture was dilutedwith acetonitrile to a specified concentration. With the LC-ES method,the yield of 2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazolinewas determined to be 65%.

EXAMPLE 11

N-(4-methoxyphenyl)-N-(2-chloro-2-propenyl)thiourea (0.26 g) and stannicchloride n-hydrate (n=4 to 5) were added to 1,3-dimethyl-2-imidazolidone(2.50 g) at room temperature with stirring, and the mixture was heatedto 90° C. and stirred at the same temperature for 1 hour. Then, 35%hydrochloric acid (0.16 g) was added to the reaction mixture at 90° C.with stirring, and the mixture was stirred at 90° C. for 11 hours. Aftercooling, water was added to the reaction mixture,which was thenneutralized by addition of sodium hydrogen carbonate and extracted withmethyl isobutyl ketone. The organic layer was washed with water. Thesolvent was removed by distillation under reduced pressure, whichafforded 0.28 g of an oily mixture of2-imino-3-(4-methoxyphenyl)-5-methyl-4-thiazoline and1,3-dimethyl-2-imidazolidone. With ¹ H-NMR spectroscopy, the yield of2-imino-3-(4-methoxyphenyl)-5-methyl-4-thiazoline was determined to be53%.

EXAMPLE 12

A mixture ofN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide (168.67g), methyl isobutyl ketone (674.70 g) and ammonium sulfide solution,yellow (518.77 g) having an S content of 6% was stirred at 50° C. for 9hours. After cooling to 20° C., water (1774.70 g) was poured into thereaction mixture, which was then shaken and fractionated with aseparatory funnel. The water layer was extracted twice with methylisobutyl ketone (53.72 g×2). The combined methyl isobutyl ketone layerwas washed with water (81.05 g) to give a methyl isobutyl ketonesolution (938.58 g) ofN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea.

To this solution (938.58 g), stannic chloride n-hydrate (n=4 to 5)(19.00 g) was added, and the mixture was stirred at 90° C. for 9 hours.After cooling below 30° C., 15% aqueous NaOH solution (150 g) was addedto the reaction mixture, which was then stirred and fractionated with aseparatory funnel. The methyl isobutyl ketone layer was washed withsaturated aqueous NaCl solution (200 g), followed by fractionation witha separatory funnel, which afforded a methyl isobutyl ketone solution(915.32 g) of2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline.

To this solution (915.32 g), 35% aqueous HCl solution (93.5 g) wasadded, and the mixture was heated to 95° C. Water was removed byazeotropic distillation, and methyl isobutyl ketone (615.30 g) wasremoved by distillation, after which the remaining methyl isobutylketone solution was gradually cooled to 20° C. The resulting crystalswere filtered and washed with methyl isobutyl ketone (110 g) cooledbelow 5° C., which afforded2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazolinehydrochloride (64 % yield on the basis ofN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide).

The present invention also provides a process of producing N-substitutedN-arylcyanamide derivatives and a process of producing N-substitutedN-arylthiourea derivatives, both of which derivatives are useful as someintermediates for the production of 2-iminothiazoline derivatives of thegeneral formula I! as depicted above.

As a conventional process of producing N-substituted N-arylcyanamidederivatives, there is, for example, a process of the following scheme asdescribed in J. Org. Chem., 29, 153-157 (1964): ##STR11## wherein Et₃ Nis triethylamine and DMF is N,N-dimethylformamide.

Even if this process is employed, however, N-substituted N-arylcyanamidederivatives cannot be obtained in satisfactory yield as shown in theabove scheme.

The present inventors have intensively studied various productionprocesses for N-substituted N-arylcyanamide derivatives of the generalformula VI! as depicted below and N-substituted N-arylthioureaderivative of the general formula VII! as depicted below with industrialbenefit. As the result, they have found that N-substitutedN-arylcyanamide derivatives of the general formula VI! as depicted belowcan be obtained with high purity in high yield by reactingN-arylcyanamide derivatives of the general formula IV! as depicted belowwith allyl halide derivatives of the general formula V! in an aproticpolar solvent in the presence of an iodide and an alkali metalcarbonate, and that N-substituted N-arylthiourea derivatives of thegeneral formula VII! as depicted below can be obtained with high purityin high yield by reacting an N-substituted N-cyanamide derivatives asobtained above with a chemical species which generates sulfide ion orhydrogensulfide ion (e.g., hydrogen sulfide; ammonium sulfide ((NH₄)₂S_(n) : the mole ratio of NH₃ and H₂ S may vary in value, such asn=1,3); sulfur (S₈) and ammonia; sulfur and organic amine).

Thus, the present invention also provides a process of producing anN-substituted N-arylcyanamide derivative of the general formula:##STR12## wherein R³, R⁴, R⁵ and X are each as defined above and R¹² isoptionally substituted aryl, the process comprising the step of reactingan N-arylcyanamide derivative of the general formula: ##STR13## whereinR¹² is as defined above, with an allyl halide derivative of the generalformula: ##STR14## wherein R³, R⁴, R⁵ and X are each as defined aboveand Y¹ is chlorine or bromine, in an aprotic polar solvent in thepresence of an iodide and an alkali metal carbonate.

Further provided is a process of producing an N-substitutedN-arylthiourea derivative of the general formula: ##STR15## wherein R³,R⁴, R⁵, R¹² and X are each as defined above, the process comprising thestep of reacting an N-substituted N-arylcyanamide derivative of thegeneral formula: ##STR16## wherein R³, R⁴, R⁵, R¹² and X are each asdefined above, with a chemical species which generates sulfide ion orhydrogensulfide ion.

In the present invention, typical examples of the R¹² are aryloptionally substituted with at least one substituent (e.g., C₁₋₈ alkyloptionally substituted with at least one halogen; C₁₋₈ alkoxy optionallysubstituted with at least one halogen; aryl, nitro, halogen, etc.).

Specific examples of the N-aryl-cyanamide derivative of the generalformula IV! used as a starting material in the present invention are asfollows:

3-(trifluoromethyl)phenylcyanamide;

3-(trifluoromethoxy)phenylcyanamide;

4-fluoro-3-(trifluoromethyl)phenylcyanamide;

3,5-dichlorophenylcyanamide;

4-methoxyphenylcyanamide; and

2-chlorophenylcyanamide.

Specific examples of the allyl halide derivative of the general formulaV! are as follows:

2,3-dichloro-1-propene;

2,3-dichloro-3-methyl-1-propene;

1,2-dichloro-2-butene;

1,2-dichloro-3-methyl-2-butene; and

2,3-dibromo-1-propene.

Specific examples of the N-substituted N-arylcyanamide derivative of thegeneral formula VI! are as follows:

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide;

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-1-methyl-2-propenyl)cyanamide;

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-butenyl)cyanamide;

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-3-methyl-2-butenyl)cyanamide;

N-(3-(trifluoromethyl)phenyl)-N-(2-bromo-2-propenyl)cyanamide;

N-(3-(trifluoromethoxy)phenyl)-N-(2-chloro-2-propenyl)cyanamide;

N-(3-(trifluoromethoxy)phenyl)-N-(2-chloro-1-methyl-2-propenyl)cyanamide;

N-(3-(trifluoromethoxy)phenyl)-N-(2-chloro-2-butenyl)cyanamide;

N-(3-(trifluoromethoxy)phenyl)-N-(2-chloro-3-methyl-2-butenyl)cyanamide;

N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide;

N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-1-methyl-2-propenyl)cyanamide;

N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-2-butenyl)cyanamide;

N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-3-methyl-2-butenyl)cyanamide;

N-(3,5-dichlorophenyl)-N-(2-chloro-2-propenyl)cyanamide;

N-(4-methoxyphenyl)-N-(2-chloro-2-propenyl)cyanamide; and

N-(2-chlorophenyl)-N-(2-chloro-2-propenyl)cyanamide.

Specific examples of the N-substituted N-arylthiourea derivatives of thegeneral formula VII! are as follows:

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea;

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-1-methyl-2-propenyl)thiourea;

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-butenyl)thiourea;

N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-3-methyl-2-butenyl)thiourea;

N-(3-(trifluoromethyl)phenyl)-N-(2-bromo-2-propenyl)thiourea;

N-(3-(trifluoromethoxy)phenyl)-N-(2-chloro-2-propenyl)thiourea;

N-(3-(trifluoromethoxy)phenyl)-N-(2-chloro-1-methyl-2-propenyl)thiourea;

N-(3-(trifluoromethoxy)phenyl)-N-(2-chloro-2-butenyl)thiourea;

N-(3-(trifluoromethoxy)phenyl)-N-(2-chloro-3-methyl-2-butenyl)thiourea;

N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea;

N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-1-methyl-2-propenyl)thiourea;

N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-2-butenyl)thiourea;

N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-3-methyl-2-butenyl)thiourea;

N-(3,5-dichlorophenyl)-N-(2-chloro-2-propenyl)thiourea;

N-(4-methoxyphenyl)-N-(2-chloro-2-propenyl)thiourea; and

N-(2-chlorophenyl)-N-(2-chloro-2-propenyl)thiourea.

Typical examples of the alkali metal carbonate used in the reaction ofN-arylcyanamide derivative of the general formula IV! with the allylhalide derivative of the general formula V! to form the N-substitutedN-arylcyanamide derivative of the general formula VI! are sodiumcarbonate and potassium carbonate. In usual cases, powder of alkalimetal carbonate is used; when fine powder of alkali metal carbonatehaving a wider surface area per specified weight (e.g., having aparticle size of 30 mesh or less) is used, the reaction rate will becomefurther high.

Typical examples of the iodide are alkali metal iodides such as sodiumiodide and potassium iodide; and alkaline earth metal iodides such ascalcium iodide and barium iodide. Sodium iodide or potassium iodide isusually used.

As the aprotic polar solvent, preferred are those having a relativepermittivity of 22 or more. Specific examples thereof areN,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),hexamethylphosphoric triamide (HMPA), sulfolane, N-metylpyrrolidone(NMP), N,N'-dimethylpropyleneurea (DMPU), 1,3-dimethyl-2-imidazolidinone(DMI), nitromethane, acetonitrile, N,N-dimethylacetamide (DMA), andmixtures thereof. DMF, DMSO and NMP are particularly preferred from anindustrial point of view.

As the allyl halide derivative of the general formula V!, those havingbromine in X are higher reactive and make the reaction time short,whereas those having chlorine in X are readily available at a smallcost, which is more favorable for practical use.

The reaction is usually carried out at a temperature of 0° to 150° C.,preferably 20° to 80° C., for 0.5 to 24 hours. The alkali metalcarbonate and the iodide are usually used at a proportion of 0.5 to 3moles and 0.01 to 1.0 mole, respectively, to one mole of the compound ofthe general formula IV!.

After completion of the reaction, the reaction mixture is concentratedas the case may be, and water is added, and if necessary, the mixture isneutralized by addition of an acid such as diluted hydrochloric acid;the neutralized mixture is subjected to an ordinary post-treatment suchas extraction with an organic solvent and concentration, and ifnecessary, any purification such as chromatography may be furtherutilized to give the desired N-substituted N-arylcyanamide derivative ofthe general formula VI!.

The reaction for conversion of the N-substituted N-arylcyanamidederivative of the general formula VI! into the N-substitutedN-arylthiourea derivative of the general formula VII! can be carriedout, for example, by the following procedures:

(a) Hydrogen sulfide gas and ammonia gas are blown at the same rate intoa solution of the N-substituted N-arylcyanamide derivative of thegeneral formula VI!I;

(b) Hydrogen sulfide gas is blown into or sulfur is added to a solutionof the N-substituted N-arylcyanamide derivative of the general formulaVI! and ammonia water;

(c) Hydrogen sulfide gas is blown into or sulfur is added to a solutionof the N-substituted N-arylcyanamide derivative of the general formulaVI! and an organic amine (e.g., triethylamine, pyridine, aniline,morpholine, etc.); or

(d) A solution of the N-substituted N-arylcyanamide derivative of thegeneral formula VI! is brought together with an ammonium sulfidesolution.

The above reactions (a) to (d) are usually carried out in a solvent.Typical example of the solvent which can be in these reactions, althoughthey are not particularly limited, are aromatic hydrocarbon solventssuch as benzene, toluene and xylene; halogenated hydrocarbon solventssuch as monochlorobenzene, chloroform and ethylene dichloride; ethersolvents such as dimethoxyethane, tetrahydrofuran and dioxane; carbonylsolvents such as acetone and methyl isobutyl ketone; alcohols such asmethanol and ethanol; N,N-dimethylformamide (DMF), dimethylsulfoxide(DMSO), water, and mixtures thereof. These reactions are usually carriedout at a temperature of 0° to 150° C. for 0.2 to 24 hours. Hydrogensulfide, sulfur or ammonium sulfide (as an S content) was used at aproportion of 1.0 to 5 moles, preferably 1.2 to 2 moles, to one mole ofthe N-substituted N-arylcyanamide derivative of general formula VI!.Also in the reactions (a) to (c), ammonia or an organic amine is used ata proportion of 0.1 to 1.2 moles to one mole of hydrogen sulfide, sulfuror ammonium sulfide.

The above reactions may be carried out by using the isolatedN-substituted N-arylcyanamide derivative of the general formula VI! orby using the reaction mixture, without further treatment, aftercompletion of the reaction of the N-arylcyanamide derivative of thegeneral of formula IV! with the allyl halide derivative of the generalformula V! to form the N-substituted N-arylcyanamide derivative of thegeneral formula VI!.

After completion of the reaction, the reaction mixture is concentratedas the case may be, and water is added, and if necessary, the mixture isneutralized by addition of an acid such as diluted hydrochloric acid;the neutralized mixture is subjected to an ordinary post-treatment suchas extraction with an organic solvent and concentration, and ifnecessary, any purification such as chromatography may be furtherutilized to give the desired N-substituted N-arylthiourea derivative ofthe general formula VII!.

The N-arylcyanamide derivative IV! used as a starting material in thepresent invention can be obtained by the conventional method. Also theallyl halide derivative of the general formula V! is commerciallyavailable or can be obtained by the conventional method.

The following Examples 13 to 16 will illustrate a process of producingN-substituted N-arylcyanamide derivatives and a process of producingN-substituted N-arylthiourea derivatives according to the presentinvention, but these examples are not to be construed to limit the scopethereof.

The purity of a product was determined from the results of NMRspectroscopy and gas chromatography and/or liquid chromatography.

The gas chromatography was carried out through a capillary column DB-1having a wide bore (manufactured by J & W Scientific) with a flameionization detector for detection.

The liquid chromatography was carried out through a reverse-phase columnODS A 212 (manufactured by Sumika Chemical Analysis Service, Ltd.) withphosphate buffered aqueous solution (pH 7.2):methanol:tetrahydrofuran=40:55:5 as an eluent and an ultraviolet-visibleabsorption detector for detection at the wavelength of 254 nm.

EXAMPLE 13

N-(3-(trifluoromethyl)phenyl)cyanamide (18.6 g) was dissolved inN,N-dimethylformamide (DMF) (93.0 g), to which powdered potassiumcarbonate (20.7 g) and potassium iodide (1.7 g) were added at roomtemperature with stirring. Further, 2,3-dichloro-1-propene (13.3 g) wasadded dropwise at room temperature with stirring. The mixture was heatedto 50° C. and stirred at the same temperature for 1 hour. After coolingto room temperature, waster was added to the reaction mixture, which wasthen extracted with ethyl acetate. The organic layer was washed withwater. The solvent was removed by distillation under reduced pressure,which afforded 25.8 g ofN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide as an oil(99% yield in appearance). The percentage areas of gas chromatographyand liquid chromatography were 98% and 99%, respectively.

¹ H-NMR (CDCl₃ /TMS) δ (ppm): 7.8-7.3 (4H, m), 5.6 (2H, s), 4.4 (2H, s).

Mass Spectrum (EI): Parent ion peak at (m/e) 260.

The N-(3-(trifluoromethyl)phenyl-N-(2-chloro-2-propenyl)cyanamide thusobtained (23.2 g) was dissolved in ethanol (380 ml), to which aqueousammonium sulfide solution, colorless (460.8 g) having an S content of0.6% was added dropwise at room temperature with stirring. The mixturewas heated to 50° C. and stirred at the same temperature for 8 hours.After cooling to room temperature, ethanol was removed by distillationunder reduced pressure, and the residue was extracted with ethylacetate. The organic layer was washed with water. The solvent wasremoved by distillation under reduced pressure, which afforded 25.2 g ofN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea as a solid(96% yield in appearance). The percentage areas of gas chromatographyand liquid chromatography were 99% and 100%, respectively.

¹ H-NMR (CDCl₃ /TMS) δ (ppm): 7.8-7.6 (4H, m), 5.9 (2H, br), 5.4 (1H,s), 5.4 (1H, s), 5.1 (2H, s).

Mass Spectrum (FD): Parent ion peak at (m/e) 294.

EXAMPLE 14

N-(3-(trifluoromethyl)phenyl)cyanamide (16.3 g) was dissolved in DMF(108.6 g), to which powdered potassium carbonate (18.4 g) was added atroom temperature with stirring. Further, 2,3-dichloro-1-propene (11.8 g)was added dropwise at room temperature with stirring. The mixture washeated to 50° C. and stirred at the same temperature for 1.5 hours. (Thepercentage area ratio of N-(3-(trifluoromethyl)phenyl)cyanamide andN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide in liquidchromatography of the reaction mixture after one hour from thetemperature rise was 81:19). Then, potassium iodide (1.7 g) was added at50° C. with stirring, and the mixture was stirred at the sametemperature for 1.5 hour. (The percentage area ratio ofN-(3-(trifluoromethyl)phenyl)cyanamide andN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide in liquidchromatography of the reaction mixture after one hour from the iodideaddition was 1:99). After cooling to room temperature, water was addedto the reaction mixture, which was then extracted with ethyl acetate.The organic layer was washed with water. The solvent was removed bydistillation under reduced pressure, which afforded 23.3 g ofN-(3-trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide as an oil(100% yield in appearance). The percentage area of gas chromatographywas 92%.

The N-(3-(trifluoromethyl)phenyl-N-(2-chloro-2-propenyl)cyanamide thusobtained (2.62 g) was dissolved in methanol (13.25 g), to which ammoniumsulfide solution, yellow (8.17 g) having an S content of 6% was addeddropwise at room temperature with stirring. The mixture was heated to50° C. and stirred at the same temperature for 7 hours. After cooling toroom temperature, water was added to the reaction mixture, which wasthen extracted with ethyl acetate. The organic layer was washed withwater. The solvent was removed by distillation under reduced pressure,which afforded 2.82 g ofN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (95% yieldin appearance). The percentage area of gas chromatography was 86%.

The N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide (2.61g) was dissolved in methyl isobutyl ketone (13.01 g), to which ammoniumsulfide solution, yellow (8.12 g) having an S content of 6% was addeddropwise at room temperature with stirring. The mixture was heated to50° C. and stirred at the same temperature for 9 hours. After cooling toroom temperature, water was added to the reaction mixture, which wasthen extracted with ethyl acetate. The organic layer was washed withwater. The solvent was removed by distillation under reduced pressure,which afforded 2.67 g ofN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea as a solid(90% yield in appearance). The percentage area of gas chromatography was85%.

A mixture of theN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide (0.8 g),sulfur (S₈) (0.15 g), methyl isobutyl ketone (5 ml) and about 30%ammonia water (4 ml) was stirred at 50° C. for 6 hours. Water (20 ml)was added to the reaction mixture, which was then extracted twice withethyl acetate (30 ml×2). The solvent was removed by distillation underreduced pressure, and the resulting crystals were washed with hexane,which afforded 0.77 g ofN-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (85%yield).

EXAMPLE 15

N-(3,5-dichlorophenyl)cyanamide (2.81 g) was dissolved in DMF (14.03 g),to which powdered potassium carbonate (3.11 g) and potassium iodide(0.26 g) were added at room temperature with stirring. Further,2,3-dichloro-1-propene (2.00 g) was added dropwise at room temperaturewith stirring. The mixture was heated to 50° C. and stirred at the sametemperature for 2.5 hours. After cooling to room temperature, DMF (9.00g) and ammonium sulfide solution, yellow (8.00 g) having an S content of6% were added dropwise to the reaction mixture at room temperature withstirring. The mixture was heated to 50° C. and stirred at the sametemperature for 4 hour. After cooling to room temperature, water wasadded to the reaction mixture, which was then extracted with ethylacetate. The organic layer was washed with water. The solvent wasremoved by distillation under reduced pressure, which afforded 4.00 g ofN-(3,5-dichlorophenyl)-N-(2-chloro-2-propenyl)thiourea as a dark redsolid (90% yield in appearance). The percentage area of liquidchromatography was 94%.

¹ H-NMR (CDCl₃ /TMS) δ (ppm): 7.5 (1H, t), 7.3 (2H, d), 5.8 (2H, br),5.4 (1H, s), 5.3 (1H, s), 5.1 (2H, s).

EXAMPLE 16

N-(4-methoxyphenyl)cyanamide (2.22 g) was dissolved in DMF (11.10 g), towhich powdered potassium carbonate (3.11 g) and potassium iodide (0.26g) were added at room temperature with stirring. Further,2,3-dichloro-1-propene (2.00 g) was added dropwise at room temperaturewith stirring. The mixture was heated to 50° C. and stirred at the sametemperature for 1.5 hours. After cooling to room temperature, ammoniumsulfide solution, yellow (8.00 g) having an S content of 6% were addeddropwise to the reaction mixture at room temperature with stirring. Themixture was heated to 50° C. and stirred at the same temperature for 3hour. After cooling to room temperature, water was added to the reactionmixture, which was then extracted with ethyl acetate. The organic layerwas washed with water. The solvent was removed by distillation underreduced pressure, which afforded 3.63 g ofN-(4-methoxyphenyl)-N-(2-chloro-2-propenyl)thiourea as a dark red solid(94% yield in appearance). The percentage area of liquid chromatographywas 94%.

¹ H-NMR (CDCl₃ /TMS) δ (ppm): 7.2 (2H, d), 7.0 (2H, d), 5.7 (2H, br),5.3 (1H, s), 5.3 (1H, s), 5.1 (2H, s), 3.9 (3H, s).

Comparative Example 1

N-(3-(trifluoromethyl)phenyl)cyanamide (5.58 g) was dissolved in toluene(90.0 g), to which powdered potassium carbonate (6.22 g), potassiumiodide (0.50 g) and tetrabutylammonium bromide (0.97 g) were added atroom temperature with stirring. Further, 2,3-dichloro-1-propene (4.00 g)was added dropwise at room temperature with stirring. The mixture washeated to 80° C. and stirred at the same temperature for 7 hours. Afterit was continued that N-(3-(trifluoromethyl)phenyl)cyanamidedisappeared, the reaction mixture was cooled to room temperature, andwater was added to the reaction mixture, which was then extracted withethyl acetate. The organic layer was washed with water. The solvent wasremoved by distillation under reduced pressure, which afforded 7.44 g ofcrude N-(3-trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide asan oil (95% yield in appearance). The percentage area of liquidchromatography was 55%.

Comparative Example 2

N-(3-(trifluoromethyl)phenyl)cyanamide (5.58 g) was dissolved in methylisobutyl ketone (90.0 g), to which powdered potassium carbonate (6.22g), potassium iodide (0.50 g) and tetrabutylammonium bromide (0.97 g)were added at room temperature with stirring. Further,2,3-dichloro-1-propene (4.00 g) was added dropwise at room temperaturewith stirring. The mixture was heated to 80° C. and stirred at the sametemperature for 7 hours. After it was confirmed thatN-(3-(trifluoromethyl)phenyl)cyanamide disappeared, the reaction mixturewas cooled to room temperature, and water was added to the reactionmixture, which was then extracted with ethyl acetate. The organic layerwas washed with water. The solvent was removed by distillation underreduced pressure, which afforded 8.21 g of crudeN-(3-trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide as an oil(1 05% yield in appearance). The percentage area of liquidchromatography was 42%.

Comparative Example 3

N-(3-(trifluoromethyl)phenyl)cyanamide (2.79 g) was dissolved in acetone(45.0 g), to which powdered potassium carbonate (3.11 g), potassiumiodide (0.25 g) and benzyltriethylammonium chloride (0.34 g) were addedat room temperature with stirring: Further, 2,3-dichloro-1-propene (2.00g) was added dropwise at room temperature with stirring. The mixture washeated to 50° C. and stirred at the same temperature for 6 hours. Afterit was confirmed the N-(3-(trifluoromethyl)phenyl)cyanamide disappeared,the reaction mixture was cooled to room temperature, and water was addedto the reaction mixture, which was then extracted with ethyl acetate.The organic layer was washed with water, which afforded a solution ofcrude N-(3-trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide. Thepercentage area of liquid chromatography was 35%.

As described in the former half of Example 13, in the reaction of anN-arylcyanamide derivative of the general formula IV! with an allylhalide derivative of the general formula V! to form an N-substitutedN-arylcyanamide derivative of the general formula VI!, the reaction ratewas remarkably reduced in cases where no iodide was added to thereaction system. As described in Comparative Examples 1 to 3, thereaction rate was also reduced and the product, N-substitutedN-arylcyanamide derivative of the general formula VI!, had a decreasedpurity in cases where the reaction was carried out in a solvent such astoluene, methyl isobutyl ketone or acetone.

What is claimed is:
 1. An N-substituted N-arylcyanamide derivative ofthe general formula: ##STR17## wherein R³, R⁴ and R⁵ are the same ordifferent, each of which is hydrogen, optionally substituted alkyl oroptionally substituted aryl; R¹² is optionally substituted aryl; and Xis halogen, with the exception ofN-phenyl-N-(2-bromo-2-propenyl)cyanamide.
 2. A compound of the formula:##STR18##
 3. The derivative of claim 1, wherein R³, R⁴ and R⁵ are thesame or different, and each is hydrogen, C₁₋₈ alkyl optionallysubstituted with at least one substituent elected from the groupconsisting of C₁₋₈ alkoxy, aryl, and C₃₋₈ cycloalkyl; and aryloptionally substituted with at least one substituent selected from thegroup consisting of C₁₋₈ alkyl, C₁₋₈ alkoxy, aryl, nitro and halogen. 4.The derivative of claim 1, wherein R¹² is aryl optionally substitutedwith at least one substituent selected from the group consisting of C₁₋₈alkyl optionally substituted with at least one halogen; C₁₋₈ alkoxyoptionally substituted with at least one halogen; aryl; nitro; andhalogen.
 5. The derivative of claim 1 which is selected from the groupconsistingof:N-(3-trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide;N-(3-trifluoromethyl)phenyl)-N-(2-chloro-1-methyl-2-propenyl)cyanamide;N-(3-trifluoromethyl)phenyl)-N-(2-chloro-2-butenyl)cyanamide;N-(3-trifluoromethyl)phenyl)-N-(2-chloro-3-methyl-2-butenyl)cyanamide;N-(3-trifluoromethyl)phenyl)-N-(2-bromo-2-propenyl)cyanamide;N-(3-trifluoromethoxy)phenyl)-N-(2-chloro-2-propenyl)cyanamide;N-(3-trifluoromethoxy)phenyl)-N-(2-chloro-1-methyl-2-propenyl)cyanamide;N-(3-trifluoromethoxy)phenyl)-N-(2-chloro -2-butenyl)cyanamide;N-(3-trifluoromethoxy)phenyl)-N-(2-chloro-3-methyl-2-butenyl)cycanmide;N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide;N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-1-methyl-2-propenyl)-cyanamide;N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-2-butenyl)cyanamide;N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(2-chloro-3-methyl-2-butenyl)-cyanamide;N-(3,5-dichlorophenyl)-N-(2-chloro-2-propenyl)cyanamide;N-(4-methoxyphenyl)-N-(2-chloro-2-propenyl)cyanamide; andN-(2-chlorophenyl)-N-(2-chloro-2-propenyl)cyanamide.